Author: Caryssa Drinkuth
Editor: Meghan Diefenbacher
Overview of Fibrodysplasia Ossificans Progressiva (FOP):
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, debilitating genetic disorder that affects an estimated 1 in 1.14 million people living in the United States.1 FOP is characterized by heterotopic ossification (HO), a process by which extra skeletal bone progressively and irreversibly develops in muscles, tendons, and ligaments.1 Episodes of HO begin in early childhood, often accompanied by symptoms including swelling, pain, stiffness, and lethargy. HO generally occurs in a characteristic and progressive anatomic pattern, beginning along the upper back and neck, though flare-ups of HO may also occur across the body in response to inflammation, influenza-like illnesses, intramuscular immunizations, or blunt soft-tissue trauma from bruises or falls.1,2 By the third decade of life, individuals with FOP are typically wheelchair bound and require assistance with daily activities1,3. Over time, accumulation of HO masses results in permanent loss of mobility and difficulty with breathing and eating, often resulting in reduced quality of life and reduced life expectancy.4 Thoracic insufficiency syndrome (TIS) resulting from HO masses surrounding the chest wall, preventing proper breathing, is the leading cause of premature death in individuals with FOP, with a median life expectancy of 56 years.3,5
Given that FOP is highly reactive to soft-tissue trauma, surgical interventions to remove HO masses are not possible, presenting a significant challenge for FOP management.4 In August 2023, Ipsen Biopharmaceutical’s Sohonos® (palovarotene) became the first and only FDA-approved oral treatment to block new HO formation in adult and pediatric individuals with FOP, representing a significant step forward in the treatment and management of FOP.6
Pathology:
Underlying Genetic Cause: While most genetic diseases are caused by specific mutations passed on from parent to child, the mutations causing the development of FOP emerge spontaneously in patients with no prior family history of the disease.2,7 The cause of the spontaneous mutations is unknown and is not associated with any particular sex, race, ethnicity, or environmental factors.1 Notably, the same single-nucleotide mutation (ACVR1R206H) in ACVR1, a gene encoding Activin A receptor type I (also known as activin-like kinase 2 (ALK2)), is observed in approximately 97% of patients identified with FOP.1,8
Normal BMP Signaling: ACVR1/ALK2 plays a key role in the regulation of bone morphogenic protein (BMP) signaling, essential for embryonic and postnatal bone and cartilage formation.8,9 Under normal conditions, BMPs bind to and activate the ACVR1 receptor.4 The activated receptor binds to and phosphorylates (adds a phosphate group to, to “activate”) intracellular BMP-responsive transcription factors known as SMADs (SMAD1/5/8).2,4,10 Phosphorylated SMAD(1/5/8) forms a complex with SMAD4 before entering the nucleus and acting to activate or repress the transcription of genes involved in cartilage formation (chondrogenesis) and bone formation (osteogenesis).10 In the absence of BMPs, Activin A binds to ACVR1 to block BMP signaling, preventing inappropriate cartilage or bone formation (Figure 1).10,11 Activin A inhibition allows normal ACVR1/BMP signaling to be tightly controlled, only becoming activated at appropriate developmental or repair stages.
BMP Signaling in FOP: In FOP, inflammatory flares, infection, or tissue damage are thought to recruit ACVR1R206H expressing fibro/adipogenic progenitors (FAPs), the major cell type of origin in HO, to the site of injury.12,13 In these FAPs, the ACVR1R206H mutation causes leaky activity of ACVR1, whereby ACVR1/BMP signaling becomes activated even in the absence of BMP ligands. The ACVR1R206Hmutation also increases ACVR1’s sensitivity to BMPs, such that lower levels of BMP ligand result in greater downstream signaling.10Furthermore, the ACVR1R206H mutation sensitizes ACVR1 to Activin A in a process referred to as neo-receptorization.8 In neo-receptorization, the normally inhibitory “stop” signal (Activin-A) flips into a stimulatory “go” signal, resulting in persistent activation of BMP signaling (Figure 1). Both the loss of inhibition and sensitization to activation of ACVR1/BMP signaling result in inappropriate downstream changes in gene transcription, causing the FAPs to reprogram and differentiate into cartilage cells (chondrocytes), and later into bone-forming cells (osteoblasts) that form HO masses (Figure 2).4,12,13 This process is further aggravated in a less-well-known manner by inflammation and hypoxia (low cellular oxygen levels), promoting further heterotopic bone formation in response to injury or infection.3
Diagnosis & Treatments:
Diagnostic Challenges: Because injuries exacerbate FOP, early detection and diagnosis are extremely important to avoid risky and unnecessary surgical procedures that may only worsen disease progression. Unfortunately, since FOP is an ultra-rare genetic disorder, clinicians are often unfamiliar with the disease or may attribute the symptoms to other causes, which can significantly delay clinical diagnosis and proper treatment. For instance, it takes about 5-6 years on average for patients to receive a FOP diagnosis.3 Additionally, approximately 90% of FOP patients are misdiagnosed, and a striking 67% of individuals with FOP undergo unnecessary surgical procedures that result in permanent harm or lifelong disability.14 Increasing clinician awareness of the classical features of FOP represents the most important step towards prompt clinical diagnosis. For instance, congenital malformation of the big toes, present in all individuals with FOP, is a unique and easily identifiable feature that can allow for quicker clinical diagnosis at earlier stages of the disease.7,14Furthermore, given that the same single mutation (ACVR1R206H ) is observed in most FOP patients, FOP is particularly suited to clinical genetic testing.14 Increased clinician awareness of the association between congenital big toe malformation and signs of early soft-tissue flare-ups or HO will be necessary to accelerate clinical diagnosis and prevent harms related to unnecessary medical procedures.
Disease Monitoring: Monitoring FOP disease progression is a significant challenge given the lack of blood tests or adequate tissue markers to measure disease severity. The cumulative analogue joint involvement scale (CAJIS), which classifies 15 joints into categories of functional, partially functional, or nonfunctional, is a simple scoring system developed to evaluate and monitor changes in a patient’s functional mobility.3 In addition, CT-scan can be used to accurately quantify heterotopic bone volume in patients with FOP, though it cannot assess bone that is still being formed.3
Current Treatments: Current treatment approaches for individuals with FOP focus on preventing soft-tissue injury and maintaining pulmonary function through the use of deep breathing exercises.3 Anti-inflammatory drugs, including high-dose corticosteroids, are often prescribed after traumatic injury or at the start of HO flare-ups.3,4 While approximately 31% patients with FOP reported an improvement of their symptoms following corticosteroid use, all evidence for corticosteroid treatment for FOP is anecdotal, and there are currently no clinical studies to evaluate the effects of corticosteroids on heterotopic bone volume.3
Non-Pharmacological Support: FOP progression, including pain from HO flare-ups, HO accumulation, and reduced mobility, may also diminish self-reported emotional health and quality of life in individuals with FOP.15 Psychological support and family therapy are recommended for patients and family members of patients diagnosed with FOP.16 FOP support groups, including the International Clinical Council on FOP (ICCFOP), International FOP Association (IFOPA), and country-specific support groups, provide safe spaces for individuals affected by FOP to share their experiences and challenges and connect with the global community.
Mechanism of Action:
Sohonos® (palovarotene), developed by Ipsen Biopharmaceuticals, Inc., is the first and currently only FDA-approved medication to reduce new bone formation (HO) in individuals with FOP. Palovarotene is a synthetic selective retinoic acid receptor γ (RARγ) agonist.4 It is well known that interactions of retinoids, biologically active vitamin A derivatives, at RARs serve an essential role in normal embryogenesis and post-natal growth. RARs are repressed in the absence of active retinoids and activated in the presence of active retinoids.4 Preclinical studies have revealed that RAR repression (occurring in the absence of retinoids), particularly involving RARγ, is essential for chondrogenesis.4 These initial preclinical findings led to the idea that the administration of a RARγ agonist, such as palovarotene, would disrupt RAR repression to prevent chondrogenesis and block HO formation in individuals with FOP. Indeed, palovarotene has been shown to reduce HO by acting on several key steps. Palovarotene is thought to primarily inhibit BMP signaling by degrading SMAD1/5/8.4,13 By degrading SMAD1/5/8, palovarotene inhibits the ACVR1/BMP signaling pathway, reducing expression of genes necessary for chondrogenesis. Palovarotene may also interfere with the recruitment of FAPs (Figure 2).4 Together, these effects may serve to counter new HO formation in individuals with FOP.
Clinical Trial:
Trial Overview and Dosing: The safety and efficacy of palovarotene were tested in MOVE, a multicenter, single-arm, open-label, phase III clinical trial.4,17 Data from participants in the MOVE trial were compared to data from FOP NHS participants who were not treated beyond the standard of care. The principal enrolled population included 99 individuals with the pathogenic ACVR1R206H variant ≥4 years old who had not experienced flare-up symptoms for at least 4 weeks before enrollment, nor received vitamin A or synthetic oral retinoids other than palovarotene before screening.17 Participants were instructed to take 5 mg oral palovarotene daily (chronic dosing) or 20 mg daily for 4 weeks, followed by 10 mg daily for 8 weeks at the onset of HO flare-ups. Both chronic and flare-up dosing were weight-adjusted for skeletally immature participants (bone age <12 years in females and <14 years in males).17
Efficacy of Palovarotene: Efficacy outcomes included assessments of functional mobility on the CAJIS at baseline and every 6 months of MOVE, as well as annualized change in new HO volume assessed by whole body CT-scan from baseline to every 6 months of MOVE.4,17At 12 months, the MOVE study was paused- statistical analyses failed to exhibit efficacy for palovarotene treatment at this timepoint. However, a review performed by the independent data safety monitoring board (DSMB) revealed that the prespecified statistical analyses were incompatible with the results of the study. Following changes to the statistical analyses, palovarotene was found to exhibit efficacy at 12 months, and the MOVE study was resumed.4,17 Post hoc analyses at 18 months revealed a 99.4% probability of reduction in new HO formation, as well as a 60% reduction in new HO volume in MOVE participants relative to NHS subjects.4,17 Changes in CAJIS were similar between MOVE participants and NHS participants receiving the standard of care, suggesting that measures such as CAJIS are less sensitive than volumetric measures, such as whole-body CT scan, over the short clinical study time period.17 Longer-term follow-up of CAJIS may provide additional insight. Overall, these findings demonstrated that palovarotene treatment shows clinical efficacy in reducing new HO formation, though these effects may only be partial.
Safety of Palovarotene: Safety outcomes were particularly important given previously known effects of retinoids to impair bone growth, particularly in participants <18 years old with open epiphyseal plates (cartilaginous growth plates at the ends of children’s long bones- particularly the knees, wrists, and hands- that do not solidify into bone until 16-18 years old).17 Participants <18 years were carefully assessed for epiphyseal abnormalities via knee and hand/wrist radiography every 6 months.17 Premature physeal closure (PPC) is considered a severe adverse event (AE) and was seen in 21 out of 57 subjects <14 years old.4,17 The severity of PPC resulted in a partial clinical hold of palovarotene dosing in subjects <14 years of age, and a final requirement restricting use of palovarotene to males >10 years old and females >8 years old, based on skeletal maturity data.4,17 Unfortunately, the understanding of specific risk factors or mechanisms of PPC following palovarotene use in patients is extremely limited.4,17 Extremely careful evaluation of risks and benefits must be considered when evaluating the potential use of palovarotene for any individual <18 years of age. Other AEs, consistent with retinoid use, included dry skin, lip dryness, alopecia, and rash, which were considered mild or moderate and were adequately managed with topical emollients.4,17 Altogether, while palovarotene appears to have a favorable safety profile in adult populations, treatment in younger individuals carries significant risks. Ultimately, this raises concerns regarding the viability of this treatment for FOP, given that intervention during adolescence (before significant HO accumulation) may be critical in improving patient outcomes.
Clinical Relevance of FOP/ Evaluating the Rationale for Clinical Usage:
The FDA approval of Sohonos® (palovarotene) is a promising step forward for many individuals living with FOP. The preclinical and clinical studies leading to the development of Sohonos® have undoubtedly improved our understanding of the cellular, molecular, and physiological basis of FOP and have promoted clinical awareness of this ultra-rare disease. Unfortunately, many challenges remain. Palovarotene exhibits some benefits for FOP patients but also has some major drawbacks. At its best, palovarotene could be beneficial for FOP patients due to its ability to partially block new HO, which could limit symptom progression or exacerbation. However, any amount of new HO in individuals with FOP has the potential to be extremely painful and disabling. At its worst, palovarotene has extreme adverse effects, including premature physeal closure in pediatric patients. Because initiating therapy early in pediatric patients with FOP is especially critical to reduce the accumulation of HO, further research will be necessary to better understand the mechanisms of both the therapeutic and adverse effects of palovarotene, particularly in children with FOP.
Future Directions of Research/Treatments Under Development:
Although palovarotene was the first pharmacotherapy developed for FOP to reach FDA approval, other pharmacotherapies, including Regeneron Pharmaceuticals’ garetosmab (REGN2477), are currently being examined for their effectiveness in reducing FOP-related HO lesions. Garetosmab, a monoclonal antibody that binds to and blocks Activin A, was granted Orphan Drug designation by the FDA in 2017.18 A recent phase III clinical trial (OPTIMA) investigating the use of garetosmab demonstrated ≥90% reductions in new HO lesions in adults with FOP.18 A second phase III clinical trial (OPTIMA-2) examining the safety and efficacy of garetosmab in adults and children with FOP is planned to take place in 2026.18 While the safety of garetosmab is still under investigation, initial trials in adults suggest an acceptable safety profile, with no serious AEs resulting in discontinuation of garetosmab treatment.18 Preclinical findings further suggest that treatment with anti-Activin A antibodies may be more efficacious than palovarotene in reducing HO formation.13 Together, these emerging findings suggest that garetosmab may address some of the safety and efficacy concerns associated with palovarotene treatment, though further research will be necessary. Given this safety profile, if FDA-approved, garetosmab may be preferred for FOP treatment in pediatric patients, while palovarotene alone or a combination of both garetosmab and palovarotene may be used to block HO in adult patients with FOP.
Publication Licenses for Figures
- Created in BioRender. Drinkuth, C. (2026) https://BioRender.com/51gpfp1
- Created in BioRender. Drinkuth, C. (2026) https://BioRender.com/lnp5g4d
References
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17. Pignolo RJ, Hsiao EC, Al Mukaddam M, et al. Reduction of New Heterotopic Ossification (HO) in the Open-Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP). J Bone Miner Res. Mar 2023;38(3):381-394. doi:10.1002/jbmr.4762
18. Regeneron Announces Positive Phase 3 Trial in Adults with Ultra-Rare Genetic Disorder Fibrodysplasia Ossificans Progressiva (FOP), Demonstrating that Garetosmab Prevents Greater than 99% of Abnormal Bone Formation. 2025. https://investor.regeneron.com/news-releases/news-release-details/regeneron-announces-positive-phase-3-trial-adults-ultra-rare